Summary of work: The aim of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent and nonhuman primate models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include dietary restriction, various pharmacologic treatments, and gene transfer via adenoviral vectors. Multiple genotypes and genetically modified mice are examined to determine possible genetic involvement in age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rats using manipulations of the cholinergic and glutamatergic neurotransmitter systems. Recently we have evaluated several novel inhibitors of butyrylcholinesterase to enhance the action of acetylcholine and observed improved maze learning in aged rats. Using transgenic mice with mutations in the amyloid precursor protein (APP) gene and the presenilin-1 (PS1) gene as a model of Alzheimers disease (AD), we have noted that treatment with acetylcholinesterase and butyrylcholinesterase inhibitors reduce production of APP and its peptide, amyloid-beta (AB). We are currently using these mice to evaluate the ability of these compounds to reduce the AB plaque formation, a pathological hallmark of AD. In the same mice we have noted that estrogen treatment can reduce plaque formation as well as microglia activation, which is also important in the pathogenesis of AD. In addition, the selective estrogen receptor modulator (SERM), raloxifine, can also reduce microglia activation following estrogen removal via ovariectomy. We have also investigated the effects of erythropoietin (EPO), which stimulates red blood cell production, on learning performance in aged rats. EPO is also produced in brain, and we have found that systemic injections of EPO can enhance performance of aged rats when give acutely. We are currently examining the effects of EPO on neurogenesis and angiogenesis. Regarding effects of calorie restriction, we have examined the behavioral performance of rats on a diet containing 2-deoxy-D-glucose (2DG) as a pharmacological intervention to &#8220;mimic&#8221; the effects of calorie restriction. We have found no evidence of behavioral neurotoxicity of long-term treatment with 2DG but rather found that 2DG treated rats were less impaired in a maze learning task following injection of the neurotoxin, kainic acid, into the brain. Currently we are assessing memory and motor performance in rhesus monkeys on calorie restriction and diets containing 2DG. (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. The lack of effects was important for confirming the safety of this compound for the treatment of stroke. Using transgenic mice with mutations in the amyloid precursor protein (APP) gene and the presenilin-1 (PS1) gene as a model of Alzheimer's disease (AD), we have noted that treatment with acetylcholinesterase and butyrylcholinesterase inhibitors reduce production of APP and its peptide, beta-amyloid (AB). We are currently evaluating the ability of these compounds to reduce the AB plaque formation in brain observed in AD. In the same mice we have noted that estrogen treatment can reduce plaque formation as well as microglia activation. Regarding the dopamine system, we have begun long-term studies to evaluate whether motor deficits observed in a null mutant mouse in which the dopamine D2 receptor has been knocked out can be ameliorated by intrastriatal injections of a D2 adenoviral vector.